The loss of vestibular function can have severe implications for general physical function and independence, and is a common consequence of aging. The heritability of balance and motor skill function has been established, but specific genes have not been identified as contributing factors, most likely due to the complexity of balance as a phenotype. The vestibular system is an important component of balance function, and thus provides a more targeted system for determining the genetic bases of balance in general. Bilateral vestibular dysfunction occurs in a significant fraction of individuals (6-16%) treated with aminoglycoside antibiotics, such as gentamicin (GM), and genetic susceptibility is indicated. The purpose of the present study is to address the genetic contribution to GM-induced vestibular dysfunction, with the goal of providing a foundation from which the susceptibility to general vestibular dysfunction (e.g., in relation to aging) can be investigated. Remarkable similarities exist between GM-related hair cell degradation in the vestibular system and age-related degradation. Thus, we will investigate the genetic susceptibility of GM-induced vestibular dysfunction in a case/control association study involving a large cohort (n = 600). Fifteen candidate genes (e.g., mitochondrial 12S rRNA, BDNF, GDNF, unconventional myosins, glutathione S-transferases, etc.) have been selected based on the accepted mechanisms of action of GM on the vestibular system, specifically hair cell degradation resulting from reactive oxygen species. We will perform both mutation and polymorphism screening for the proposed candidate genes. Specific loci and their combinations will be compared between 300 cases and 300 ethnicity-matched controls to identify susceptibility genes for GM-induced vestibular dysfunction. In addition to providing an immediate and significant clinical impact for patients being considered for aminoglycoside therapy, the present work will provide important preliminary information about the genetic aspects of vestibular function in general, which we predict will have relevance for the susceptibility to age-related vestibular dysfunction and balance impairment. The proposed project will generate important pilot data related to the genetics of vestibular dysfunction, thus fitting within the R21 grant mechanism.